Citrate solutions



Patented Nov. 21, 1933 1,936,364 CITRATE SOLUTIONS Richard Pasternackand Clinton I. Ammo 1 Brooklyn, N. ,Y., assi gnors to Charles Pfizer &Company, Brooklyn, N. Y., a corporation of New Jersey No Drawing.Application August 22, 1930 Serial No. 477,186

14 Claims.

This invention relates to citrate solutions and more particularly tosolutions of magnesium citrate and magnesium citrate compositions.

The formula of the Pharmacopoeia of the 5 United States calls for 35gms. of citric for magnesium citrate solution acid, 15 gms. of magnesiumcarbonate (containing 39.2% MgO) and 2.5 gins. of potassium bicarbonateor 2.1 gms. of sodium bicarbonate, per 350 cos. of solution. In

this formula the to citric acid is proportion of magnesium oxide suchthat it allows the formation of di-basic magnesium citrate, MgHCsHsOt,

in stable solution,

of the total citric acid introduced being left in excess as free citricacid.

Any material reduction in the excess of citric acid from that given inthe formula will result in a solution which gradually deposits insolubletri-basic magnesium citrate, Mg3(CeH5O7)2.9H2O. That the-free citricacid in the U. S. P. formula cannot be materially reduced without riskof pre-= cipitation was determined as follows: 29.8 gms.

oi Mgs(CsH5O7)2-9H2O, the amount equivalent to 15 gms. of 39.2% MgO),amount of water necessary to give 350 cc. of solution as per wascontinued and citric complete solution was effected. of citric acid wererequired. Mg3(CsH5O7) of citric acid essary to neu carbonate us amountof c solution is magnesium carbonate (containing was boiled in 310 cc.of Water, the

the U. S. P. formula. The boiling acid was added until 12.5 to 13 gms.As 29L8 gms. of

291-120 are equivalent to 20% gms. and 1.75 gms. of citric acid arenectralize the 2.5 gms. of potassium bied in the U. S. P. formula, thetotal itrio acid required to obtain a stable 34.65-35.15 gms.,approximately the amount called for in the U. S. P. formula.

The high acidity of the magnesium citrate solution due to the freecitric acid gives the product an excessively sour taste.

An object of the present invention is to provide a palatable magnesiumcitrate solution of materially lower acidity than heretofore obtained.

A further object is the provision of a stable magnesium citrate solutionof greater conoentration than heretofore A still fur is to provi.

known.

ther object of the present invention de a dry stable mixture comprisingmagnesium carbonate or oxide, citric acid, and

a tribasic magnesium citrate solvent which may be converted into animproved magcompound,

nesium citrate solution by the addition of water and the remainingcommonly employed ingredients of magnesium citrate solutions.

Another object of the present invention is to provide'a dry stableproduct resulting tram the reaction of magnesium carbonate or oxide withcitric acid and a tribasic magnesium citrate solvent compound.

We have discovered that gluconic acid has the property of preventingprecipitation of tribasic magnesium citrate, and can be substituted forthe excess free citric acid heretofore used in U. S. P. magnesiumcitrate solutions. Thereby a stable, less acid, and more palatablesolution can be produced and also oneof higher concentration. Themagnesium carbonate or oxide can now be mixed dry with the dry citricacid and gluconic acid lactone, said lactone being an equivalent ofgluconic acid for this purpose but better adapted for use in a drymixture as it is a stable, solid compound, and kept ready for making thesolution when required.

As shown above, it required about 13 gms. of citric acid to dissolve29.8 gms. of

in 310 cc. of water on boiling. The same quantity of Mg3(CtH5O7)2-9H2Ois also dissolvedin 310 cc. of water upon the addition of 13 gms. ofgluconic acid, but 13 gms. of gluconic acid are equivalent in acid valueto only 4.64 gms. of citric acid. Hence the solution produced by 13 gms.of gluconic acid has only about one third of the titrable acidity of theU. S. P. product using only citric acid. The magnesium citrate solutionproduced by using gluconic acid to replace some or all of the freecitric acid has only a mildly acid taste due to its much lower aciditythan the U. S. P. product but the therapeutic value of the productremains unchanged, as it is in no way influenced by the acidity of thesolution.

To illustrate the invention, the following ex ample of a formula for acitrate of magnesia solution of U. S. P. strength is given:

cient to make 350.0 cos. sol.

The citric and gluconic acids are dissolved in 150 cc. of hot distilledwater. 15 gms. magnesium carbonate or about 6 gms. otmagnesium oxidenixed with 100 cc. of distilled water areadded to ;he acid solutionwhich is stirred until'the magnesium compound is dissolved. The syrup orsugaris then introduced and the solution is heated to its boilingpoint-whereupon the oil of lemon, which has been triturated with thetale, is immediately added and the liquid is filtered, while hot,

into a 350 cc. capacity bottle. Distilled water is added to fill thebottle and the sodium bicarbonate tablet is dropped in and the bottleimmediately stoppered. The bottle is then immersed for 30 minutes in awater bath at 90 C. to sterilize the solution.

A stable solution of magnesia in citric acid and gluconic acid,containing more than 2 gms. of MgO per 100 cc. of solution can beprepared in this manner whereas a stable solution of magnesia in citricacid alone, containing more than 1.8 gms. of MgO per 100 00., could notheretofore be prepared, and the stability of a solution containing eventhat amount of MgO was not very great. V

The above formula is merely illustrative and the ingredients andproportions of ingredients may be varied considerably. The amount ofgluconic acid may be increased and the amount of sugar may be decreasedto suit the taste without affecting the stability of the solution. Alsothe amount of water may be reduced by more than one half to give agreatly more, concentrated solution. This is a material advantage overthe U. S. P. product as it allows a much more concentrated stablemagnesium citrate solution to be marketed, thus effecting aconsiderablesaving in the cost of containers and shipping, and allowing asubstantial reduction in the volume of an. efiective dose of thesolution.

In place of gluconic acid, any of the known gluconic acid lactones suchas the beta, gamma, or delta lactone, may be used and the term gluconicacid lactone, as usedherein, is meant to include the known gluconic acidlactones." As 0.91 gms. of gluconic acid lactone are equivalent to 1 gm.of gluconic acid (100% basis) ,the amount of lactone used in place ofgluconic acid is diminished accordingly.

Gluconic acid'lactone is a stablesolid and it may be mixed withmagnesium carbonate or oxide and citric acid and, if desired, with theother I solid ingredients of magnesium citrate solutions, and then bestored without deterioration. .This dry stable mixture is advantageousas it can be shipped to druggists or the like who can store it untilneeded and then mixit with water and the other necessary ingredients,and bottle the solution. The dry mixture may also be soldto theconsumerwho can' make up the solution therefrom. For example, adrycomposition comprising magnesium carbonate (39.2% MgO), an-' hydrouscitric acid, and gluconic acid lactone in the proportion by weight of:20:12- can be stored and shipped without deterioration and a citrate ofmagnesia solution of U. S. P. strength can readily be made by adding therequired 5 amount-of water,- sweetening and fiavouring, and bicarbonate.Shipping and storage of the dry mixture is advantageous as the waterwhich gives the solution most of its bulk and weight, need not be addeduntil shortly before the solution is to be delivered to the consumer orthe dry mixture can be sold tothe consumer who may make up the-solutionwithout difficulty.

r A dry mixture comprising magnesium carbon-I ate or oxide, gluconicacid lactone, and a free 75 flowing granular substantiallyanhydrouscitric ties is made as follows:

acid obtained by exposing ccmminuted citric acid containing its water ofcrystallization in shallow layers and applying dry air at a temperatureof between C. and C. until the acid becomes granular and free flowing isparticularly advantageous.- Due to the free flowing, granularcharacteristic of the citric acid, a uniform mixture of theingredients'is easier to obtain and also the handling and measuring ofthe dry mixture is facilitated.

Another dry mixture of advantageous .proper- 220 parts by weight citricacid (with 1 mol H2O), 59-parts by weight magnesium oxide (on 100%basis), 130 parts by weight gluconic acid (on 100% basis), are dissolvedin 800 parts of water. The resulting solution is filtered and evaporatedto dryness, preferably in vacuo. A,

dry amorphous product is thus obtained, which may be ground into a finewhite powder. We have not determined the exact chemical constitution ofthis new composition but it contains the magnesia combined with bothcitric and gluconic acid, that is, it is, in efiect, amagnesiumglucono-citrate.

This new product is stable under ordinary conditions of storage. It isvery soluble in water,

so that even solutions of a syrupy consistencycan be-prepared. About 40gms. of the dry product mixed with a suitable amount of sweetening,flavoring and bicarbonate is the equivalent in strength of one bottle ofU. S. P. citrate of mag-. nesia solution. This dry mixture can bemarketed directly to the consumer, who may dissolve it in any desiredquantity of water.

' The invention claimed is:

1. Product comprising a stable aqueous solution of magnesium citrate andgluconic acid, containing substantially no excess of citric acid.

2. A new product comprising a stable solution of magnesia in citric andgluconic'acids, containing more than 1.8 gms. of MgO per 100 cc. ofsolution. v

3. A dry product comprising a member selected a from the groupconsisting of magnesium car- 120 bonate and magnesium oxide, citricacid, and

gluconic acid lactone.

4. A dry product comprising about 15 parts by weight of magnesiumcarbonate, 23 parts by weight of citric acid, and 12 parts by weight ofgluconic acid lactone. r

5. A dry product comprising about 6 parts by weight of magnesium oxide,23 parts by weight of citric acid, and 12 parts by weight of gluconicacid lactone. p r

6. Product comprising a stable aqueous solution of magnesia and citricandgluconic acids in the ratio of 6 parts of magnesia to at least 20parts of anhydrous citric acid and at least 12 parts of gluconic acid. a

i '7. A new product'comprising a stable aqueous solution containing thereaction product, per 350 cc. of solution, of about 6.0 gms. ofmagnesia, 23.0 gms. of citric acid, 13.0 gms. of gluconic acid, sugar,flavoring, and analkalimetal bicarbonate 140 equivalent to 1.75 gms.citric acid, said product having a therapeutic value equivalent to theU. S. P. product. v

8. A stabilized solution containing thereaction product of about 6 gms.of magnesia, 23.0 gms. 5

product from the reaction in aqueous solution of magnesia and citric andgluconic acids in the ratio to 6 parts of magnesia of at least 20 partsof anhydrous citric acid and at least 12 parts of gluconic acid.

14. A dry product comprising magnesia, citric and gluconic acids in theratio, to 6 parts of magnesia, of at least 20 parts of anhydrous citricacid and at least 12 parts of gluconic acid.

RICHARD PASTERNACK.

